1. Field of the Invention
The present invention comprises certain proline derivatives which are useful as human leukocyte elastase inhibitors, e.g. in the treatment of tissue degenerative diseases such as pulmonary emphysema, atherosclerosis, rheumatoid and osteo arthritis in humans, methods for their use, processes used for their synthesis, intermediates useful in such syntheses and pharmaceutical compositions prepared with such derivatives.
2. Description of the Prior Art
Peptide aldehyde inhibitors of both porcine pancreatic elastase (PPE) and human leukocyte elastase (HLE) have been previously reported. For example, Thompson, Biochemistry, 1973, vol. 12, pages 47-51 has described the synthesis of two peptide aldehyde inhibitors of porcine pancreatic elastase. One of these was N-acetyl-L-alanyl-L-prolyl-L-alaninal.
Szabo et al., Acta Biochimica et Biophysica Academiae Scientiarum Hungaricae, 1982, vol. 17 (1-2), page 98, reports the synthesis of five peptide aldehyde compounds, all of which proved to be inhibitors for pancreatic elastase and human leukocyte elastase. The most potent HLE inhibitor reported was N-succinyl-D-phenylalanyl-L-prolyl-L-valinal; this compound produced 10-100 times stronger inhibition (K.sub.i =4.times.10.sup.-5) than the other four aldehydes.
Although various peptide aldehydes have been reported in the literature, none has been found to be clinically useful in the treatment of any tissue degenerative disease to date.
It is generally accepted that proteolysis of lung elastin by elastases, such as human leukocyte elastase (HLE) and cathespin G, which are released from the granular fraction of polymorphonuclear leukocytes, is responsible for a major part of the tissue degradation seen in pulmonary emphysema. It is also believed that elastases are similarly involved in the initiation and progression of various other tissue degenerative diseases, such as atherosclerosis, osteo-arthritis and rheumatoid arthritis. Accordingly, the potent elastase inhibitors of this invention may be used in the treatment and/or prevention of any one or more of the above mentioned diseases. They may also be used as research tools in pharmacological and related studies.